Background: About 1/3 of patients with TNBC who receive preoperative therapy will experience a pathological complete response (pCR). Patients with residual disease have a markedly inferior overall survival (OS) compared to those who experience pCR. Recently, the CREATE-X trial demonstrated an improvement in disease free survival (DFS) and OS for post-neoadjuvant capecitebine; although the addition of capecitebine to standard therapy has not previously improved outcome across other non-selected adjuvant or neo-adjuvant trials. Prior data have also demonstrated that the residual tumors are genomically diverse and that these genetic changes are reflected at time of relapse.
Trial Design: This trial is a randomized phase II trial to determine whether a genomically guided therapy in the setting of incomplete response to standard neoadjuvant therapy will improve outcomes compared to standard of care. DNA from archived tumor samples collected at the time of surgery will be extracted and sequenced. The sequencing data will be interrogated for known genomic drivers of sensitivity or resistance to existing FDA approved agents. A cancer genomic tumor board (CGTB) will consider the genomic data along with the patient's prior treatment history, toxicities, and comorbidities and select the optimal therapy. Participants with a CGTB recommendation will be randomized to Experimental Arm A (genomically directed monotherapy) or Control Arm B (standard of care). Participants may have no CGTB recommendation either because sequencing did not identify a matched drug or because the drug was contraindicated and will be assigned to Control Arm B.
Eligibility criteria: Patients must have histologically confirmed TNBC with completion of all definitive local therapy and no evidence of metastatic disease. There must be significant residual disease characterized by >2cm primary tumor, or lymph node positivity or RCB classification II or III. An FFPE tumor block with tumor cellularity >20% is required. All patients must have completed preoperative chemotherapy including a taxane or anthracycline or both.
Specific aims: The Primary Aim is to compare 2-year DFS with a genomically directed therapy vs. standard of care. Secondary Aims include 1-year DFS, 5-year OS, collection of archival specimens for correlative studies, and to describe toxicities. Exploratory Aims are to describe the evolution of genomically directed therapies during the course of the study and to evaluate the drug specific effect on efficacy and toxicity.
Statistical methods: In order to detect an improvement in the fraction of patients free from disease at 2-year from 40% in the control Arm B to 63.2% in the genomically directed Experimental Arm A (corresponding to an HR=0.5), 136 participants will have 80% power to detect a difference in DFS using a two-side log-rank test with 0.05 level of significance.
Present accrual/target accrual: 38 accrued of 136 to be randomized.
Citation Format: Schneider B, Miller KD, Badve S, O'Neil B, Helft P, Chitambar C, Falkson C, Nanda R, McCormick M, Danso M, Blaya M, Langdon R, Lippman M, Paplomata E, Walling R, Thompson M, Robin E, Aggarwal L, Shalaby I, Canfield V, Adesunloye B, Lee T, Daily K, Ma C, Erban J, Radhakrishnan N, Bruetman D, Graham M, Reddy NA, Lynce FC, Radovich M. BRE12-158: A phase II randomized controlled trial of genomically directed therapy after preoperative chemotherapy in patients with triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-04-01.